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. 1999 Jan;58(1):42–48. doi: 10.1136/ard.58.1.42

Anti-perinuclear factor compared with the so called "antikeratin" antibodies and antibodies to human epidermis filaggrin, in the diagnosis of arthritides

C Vincent 1, F de Keyser 1, C Masson-Bessiere 1, M Sebbag 1, E Veys 1, G Serre 1
PMCID: PMC1752764  PMID: 10343539

Abstract

OBJECTIVE—Antiperinuclear factor (APF), "antikeratin antibodies" ("AKA"), and antibodies to human epidermis filaggrin (AFA), are highly specific serological markers of rheumatoid arthritis (RA), which recognise epitopes on various isoforms of (pro)filaggrin. It was proposed that these antibodies are globally named antifilaggrin autoantibodies. Here the diagnostic value of the detection of each one is compared and the overlap between the three tests evaluated.
METHODS—492 serum samples were tested, including 279 RA serum samples, taken from patients in France and Belgium. APF and "AKA" titres were estimated by indirect immunofluorescence, and AFA titres by immunoblotting on filaggrin enriched human epidermis extracts.
RESULTS—By a convenient choice of the positivity thresholds, the diagnostic sensitivity and specificity of the tests were shown to be similar (0.52 and 0.97, respectively). Although the antibody titres were strongly correlated, the associations APF-AFA or AFA-"AKA" permitted more than 52% or 55% of RA to be diagnosed, with a specificity of 0.99.
CONCLUSION—APF, "AKA", and AFA detection have a similar diagnostic value. However, because the three tests do not totally overlap, associating APF with "AKA" or AFA with "AKA" can improve diagnostic sensitivity. None of the three antigens used bear all the epitopes recognised by anti-filaggrin autoantibodies.

 Keywords: rheumatoid arthritis; antifilaggrin autoantibodies; antiperinuclear factor; antikeratin antibodies

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Figure 1  .

Figure 1  

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Titre distribution of APF, "AKA", and AFA in RA and control serum samples. APF titre is given as U/ml. "AKA" and AFA titres correspond to a semiquantitative evaluation of the immunoreactivity by indirect immunofluorescence on rat oesophagus cryosections and by immunoblotting on filaggrin enriched human epidermis extract, respectively. Black bars: RA samples; empty bars: control samples. The number of samples is indicated for the bars off the scale.

Figure 2  .

Figure 2  

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Receiver operating characteristic (ROC) curves of APF, "AKA", and AFA detection. For the three tests, the diagnostic sensitivity (rate of true positives) is plotted compared with 1-specificity (rate of false positive). The portion of curves corresponding to the lowest rate of false positives shows differences between the diagnostic sensitivities of the tests when the specificity ranges from 0.95 to 1.00. 

Figure 3  .

Figure 3  

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Correlation between the titres of APF, "AKA", and AFA in RA and control serum samples. The correlation coefficients (r) were computed only for RA samples. The three correlation coefficients are highly significant (p<10-6). Black dots: RA samples; empty dots: control samples.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aho K., von Essen R., Kurki P., Palosuo T., Heliövaara M. Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process. J Rheumatol. 1993 Aug;20(8):1278–1281. [PubMed] [Google Scholar]
  2. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  3. Feltkamp T. E., Berthelot J. M., Boerbooms A. M., Geertzen H. G., Hoet R., De Keyser F., van Venrooij W. J., Verbruggen G., Veys E. M., Youinou P. Interlaboratory variability of the antiperinuclear factor (APF) test for rheumatoid arthritis. Clin Exp Rheumatol. 1993 Jan-Feb;11(1):57–59. [PubMed] [Google Scholar]
  4. Girbal E., Sebbag M., Gomès-Daudrix V., Simon M., Vincent C., Serre G. Characterisation of the rat oesophagus epithelium antigens defined by the so-called 'antikeratin antibodies', specific for rheumatoid arthritis. Ann Rheum Dis. 1993 Oct;52(10):749–757. doi: 10.1136/ard.52.10.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gomès-Daudrix V., Sebbag M., Girbal E., Vincent C., Simon M., Rakotoarivony J., Abbal M., Fournié B., Serre G. Immunoblotting detection of so-called 'antikeratin antibodies': a new assay for the diagnosis of rheumatoid arthritis. Ann Rheum Dis. 1994 Nov;53(11):735–742. doi: 10.1136/ard.53.11.735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hajiroussou V. J., Skingle J., Gillett A. P., Webley M. Significance of antikeratin antibodies in rheumatoid arthritis. J Rheumatol. 1985 Feb;12(1):57–59. [PubMed] [Google Scholar]
  7. Harding C. R., Scott I. R. Histidine-rich proteins (filaggrins): structural and functional heterogeneity during epidermal differentiation. J Mol Biol. 1983 Nov 5;170(3):651–673. doi: 10.1016/s0022-2836(83)80126-0. [DOI] [PubMed] [Google Scholar]
  8. Hoet R. M., Boerbooms A. M., Arends M., Ruiter D. J., van Venrooij W. J. Antiperinuclear factor, a marker autoantibody for rheumatoid arthritis: colocalisation of the perinuclear factor and profilaggrin. Ann Rheum Dis. 1991 Sep;50(9):611–618. doi: 10.1136/ard.50.9.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hoet R. M., Voorsmit R. A., Van Venrooij W. J. The perinuclear factor, a rheumatoid arthritis-specific autoantigen, is not present in keratohyalin granules of cultured buccal mucosa cells. Clin Exp Immunol. 1991 Apr;84(1):59–65. doi: 10.1111/j.1365-2249.1991.tb08124.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Janssens X., Veys E. M., Verbruggen G., Declercq L. The diagnostic significance of the antiperinuclear factor for rheumatoid arthritis. J Rheumatol. 1988 Sep;15(9):1346–1350. [PubMed] [Google Scholar]
  11. Johnson G. D., Carvalho A., Holborow E. J., Goddard D. H., Russell G. Antiperinuclear factor and keratin antibodies in rheumatoid arthritis. Ann Rheum Dis. 1981 Jun;40(3):263–266. doi: 10.1136/ard.40.3.263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kataaha P. K., Mortazavi-Milani S. M., Russell G., Holborow E. J. Anti-intermediate filament antibodies, antikeratin antibody, and antiperinuclear factor in rheumatoid arthritis and infectious mononucleosis. Ann Rheum Dis. 1985 Jul;44(7):446–449. doi: 10.1136/ard.44.7.446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kirstein H., Mathiesen F. K. Antikeratin antibodies in rheumatoid arthritis. Methods and clinical significance. Scand J Rheumatol. 1987;16(5):331–338. doi: 10.3109/03009748709102504. [DOI] [PubMed] [Google Scholar]
  14. Kurki P., Aho K., Palosuo T., Heliövaara M. Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease. Arthritis Rheum. 1992 Aug;35(8):914–917. doi: 10.1002/art.1780350810. [DOI] [PubMed] [Google Scholar]
  15. Mallya R. K., Young B. J., Pepys M. B., Hamblin T. J., Mace B. E., Hamilton E. B. Anti-keratin antibodies in rheumatoid arthritis: frequency and correlation with other features of the disease. Clin Exp Immunol. 1983 Jan;51(1):17–20. [PMC free article] [PubMed] [Google Scholar]
  16. NIENHUIS R. L., MANDEMA E. A NEW SERUM FACTOR IN PATIENTS WITH RHEUMATOID ARTHRITIS; THE ANTIPERINUCLEAR FACTOR. Ann Rheum Dis. 1964 Jul;23:302–305. doi: 10.1136/ard.23.4.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ordeig J., Guardia J. Diagnostic value of antikeratin antibodies in rheumatoid arthritis. J Rheumatol. 1984 Oct;11(5):602–604. [PubMed] [Google Scholar]
  18. Paimela L., Gripenberg M., Kurki P., Leirisalo-Repo M. Antikeratin antibodies: diagnostic and prognostic markers for early rheumatoid arthritis. Ann Rheum Dis. 1992 Jun;51(6):743–746. doi: 10.1136/ard.51.6.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Palosuo T., Lukka M., Alenius H., Kalkkinen N., Aho K., Kurki P., Heikkilä R., Nykänen M., von Essen R. Purification of filaggrin from human epidermis and measurement of antifilaggrin autoantibodies in sera from patients with rheumatoid arthritis by an enzyme-linked immunosorbent assay. Int Arch Allergy Immunol. 1998 Apr;115(4):294–302. doi: 10.1159/000069460. [DOI] [PubMed] [Google Scholar]
  20. Quismorio F. P., Jr, Kaufman R. L., Beardmore T., Mongan E. S. Reactivity of serum antibodies to the keratin layer of rat esophagus in patients with rheumatoid arthritis. Arthritis Rheum. 1983 Apr;26(4):494–499. doi: 10.1002/art.1780260407. [DOI] [PubMed] [Google Scholar]
  21. Schellekens G. A., de Jong B. A., van den Hoogen F. H., van de Putte L. B., van Venrooij W. J. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998 Jan 1;101(1):273–281. doi: 10.1172/JCI1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Scott D. L., Delamere J. P., Jones L. J., Walton K. W. Significance of laminar antikeratin antibodies to rat oesophagus in rheumatoid arthritis. Ann Rheum Dis. 1981 Jun;40(3):267–271. doi: 10.1136/ard.40.3.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sebbag M., Simon M., Vincent C., Masson-Bessière C., Girbal E., Durieux J. J., Serre G. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1995 Jun;95(6):2672–2679. doi: 10.1172/JCI117969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Serre G., Vincent C., Viraben R., Soleilhavoup J. P. Natural IgM and IgG autoantibodies to epidermal keratins in normal human sera. I: ELISA-titration, immunofluorescence study. J Invest Dermatol. 1987 Jan;88(1):21–27. doi: 10.1111/1523-1747.ep12464810. [DOI] [PubMed] [Google Scholar]
  25. Simon M., Girbal E., Sebbag M., Gomès-Daudrix V., Vincent C., Salama G., Serre G. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called "antikeratin antibodies," autoantibodies specific for rheumatoid arthritis. J Clin Invest. 1993 Sep;92(3):1387–1393. doi: 10.1172/JCI116713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Simon M., Sebbag M., Haftek M., Vincent C., Girbal-Neuhauser E., Rakotoarivony J., Sommé G., Schmitt D., Serre G. Monoclonal antibodies to human epidermal filaggrin, some not recognizing profilaggrin. J Invest Dermatol. 1995 Sep;105(3):432–437. doi: 10.1111/1523-1747.ep12321148. [DOI] [PubMed] [Google Scholar]
  27. Simon M., Vincent C., Haftek M., Girbal E., Sebbag M., Gomès-Daudrix V., Serre G. The rheumatoid arthritis-associated autoantibodies to filaggrin label the fibrous matrix of the cornified cells but not the profilaggrin-containing keratohyalin granules in human epidermis. Clin Exp Immunol. 1995 Apr;100(1):90–98. doi: 10.1111/j.1365-2249.1995.tb03608.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Smit J. W., Sondag-Tschroots I. R., Aaij C., Feltkamp T. E., Feltkamp-Vroom T. M. The antiperinuclear factor: II. A light microscopical and immunofluorescence study on the antigenic substrate. Ann Rheum Dis. 1980 Aug;39(4):381–386. doi: 10.1136/ard.39.4.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sondag-Tschroots I. R., Aaij C., Smit J. W., Feltkamp T. E. The antiperinuclear factor. 1. The diagnostic significance of the antiperinuclear factor for rheumatoid arthritis. Ann Rheum Dis. 1979 Jun;38(3):248–251. doi: 10.1136/ard.38.3.248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vincent C., Serre G., Basile J. P., Lestra H. C., Girbal E., Sebbag M., Soleilhavoup J. P. Subclass distribution of IgG antibodies to the rat oesophagus stratum corneum (so-called anti-keratin antibodies) in rheumatoid arthritis. Clin Exp Immunol. 1990 Jul;81(1):83–89. doi: 10.1111/j.1365-2249.1990.tb05295.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Vincent C., Serre G., Fournié B., Fournié A., Soleilhavoup J. P. Natural IgG to epidermal cytokeratins vs IgG to the stratum corneum of the rat oesophagus epithelium, so-called 'antikeratin antibodies', in rheumatoid arthritis and other rheumatic diseases. J Autoimmun. 1991 Jun;4(3):493–505. doi: 10.1016/0896-8411(91)90161-5. [DOI] [PubMed] [Google Scholar]
  32. Vincent C., Serre G., Lapeyre F., Fournié B., Ayrolles C., Fournié A., Soleilhavoup J. P. High diagnostic value in rheumatoid arthritis of antibodies to the stratum corneum of rat oesophagus epithelium, so-called 'antikeratin antibodies'. Ann Rheum Dis. 1989 Sep;48(9):712–722. doi: 10.1136/ard.48.9.712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Vincent C., Simon M., Sebbag M., Girbal-Neuhauser E., Durieux J. J., Cantagrel A., Fournié B., Mazières B., Serre G. Immunoblotting detection of autoantibodies to human epidermis filaggrin: a new diagnostic test for rheumatoid arthritis. J Rheumatol. 1998 May;25(5):838–846. [PubMed] [Google Scholar]
  34. Vivino F. B., Maul G. G. Histologic and electron microscopic characterization of the antiperinuclear factor antigen. Arthritis Rheum. 1990 Jul;33(7):960–969. doi: 10.1002/art.1780330707. [DOI] [PubMed] [Google Scholar]
  35. Youinou P., Le Goff P., Colaco C. B., Thivolet J., Tater D., Viac J., Shipley M. Antikeratin antibodies in serum and synovial fluid show specificity for rheumatoid arthritis in a study of connective tissue diseases. Ann Rheum Dis. 1985 Jul;44(7):450–454. doi: 10.1136/ard.44.7.450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Youinou P., Le Goff P., Dumay A., Lelong A., Fauquert P., Jouquan J. The antiperinuclear factor. I. Clinical and serologic associations. Clin Exp Rheumatol. 1990 May-Jun;8(3):259–264. [PubMed] [Google Scholar]
  37. Youinou P., Serre G. The antiperinuclear factor and antikeratin antibody systems. Int Arch Allergy Immunol. 1995 Aug;107(4):508–518. doi: 10.1159/000237093. [DOI] [PubMed] [Google Scholar]
  38. Young B. J., Mallya R. K., Leslie R. D., Clark C. J., Hamblin T. J. Anti-keratin antibodies in rheumatoid arthritis. Br Med J. 1979 Jul 14;2(6182):97–99. doi: 10.1136/bmj.2.6182.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. von Essen R., Kurki P., Isomäki H., Okubo S., Kautiainen H., Aho K. Prospect for an additional laboratory criterion for rheumatoid arthritis. Scand J Rheumatol. 1993;22(6):267–272. doi: 10.3109/03009749309095137. [DOI] [PubMed] [Google Scholar]

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